Olanzapine is a thienobenzodiazepine of formula (I):
that acts as an antagonist on dopamine receptors D1, D2, D3, D4, and D5; of serotonin 5-HT2 and 5-HT3; alpha-1-adrenergics, cholinergics and H1 histaminergics.
Olanzapine is an antipsychotic compound that is marketed in several dosages (2.5, 5, 7.5, 10, 15 mg) for oral administration, or 10 mg for injection for the treatment of schizophrenia, bipolar disorders or manic episodes. However, olanzapine Form I tends to be metastable and to produce an undesirable coloration, while suitable homogeneity of the final solid formulation also has to be ensured.
This coloration arises when certain excipients, including mixtures of powders, come into contact with the olanzapine and increase under ambient environmental conditions of the air, at high temperatures and in wet environments. Although this coloration does not mean an increase in total related substances, it is not acceptable for commercial purposes.
Thus, Spanish patent ES2164837T3 (equivalent to European patent EP 733367) has the object of providing solid oral formulations of olanzapine as active ingredient, thoroughly intermixed with a filler agent, a binder, a disintegrant, a dry binder to ensure appropriate friability and a lubricant; where said solid oral formulation is coated with a polymer selected from among the group that comprises: hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrolidone, copolymer of dimethylaminoethyl methacrylate and methyl acrylate, copolymer of ethyl acrylate and methyl methacrylate, methylcellulose and ethylcellulose, which provides uniformity and physical stability and effectively prevents the phenomenon of undesirable coloration of the formulation.
In particular, said patent precludes the use of a polymer that contains polyethylene glycol. Also according to said patent, it is specially preferred that the formulation contains the most stable anhydrous form of olanzapine referred as Form II. The preferred process described for its preparation is by granulation in aqueous medium.
Moreover, patent application WO04/035027 proposes a highly stable formulation, free from coloration and having good uniformity. In particular, said application describes a formulation that includes a mixture of (a) olanzapine or a salt thereof as active substance; (b) a monosaccharide and/or oligosaccharide; (c) a polysaccharide and, optionally, other ingredients. The preferred oligosaccharide is lactose and the preferred polysaccharide cellulose, and it is preferable for the formulation not to contain microcrystalline cellulose, since this form of cellulose is hygroscopic and can have an adverse effect on the stability of the composition.
In accordance with said document, the phenomenon of coloration is believed to be caused by the formation of hydrates of olanzapine so that, as a consequence, in order to avoid their formation the method for obtaining a formulation that contains olanzapine must be carried out without using solvents. Said formulation is thus prepared by direct compression once the olanzapine or one of its salts has been mixed homogeneously with the excipients mentioned.
Patent application WO05/009407 discloses two ways of preventing the problem of undesirable coloration of formulations containing olanzapine.
In particular, it discloses the coating of particles of olanzapine with lactose and/or mannitol and, optionally, with other pharmaceutically acceptable excipients selected from among at least one binder selected from a polymer of cellulose or polymers of vinylpyrrolidone, at least one disintegrant, at least one filler agent and at least one lubricant. It also proposes coating the tablets of olanzapine with one or more excipients selected from the group that includes carrageenate, sodium alginate, sodium carboxymethylcellulose, a polyvinyl alcohol-polyethylene glycol graft copolymer or a titanium oxide-talc mixture.
The utilisation of polymers insoluble in water that protect the core from moisture has the disadvantage of delaying release of the active substance in the physiological medium. Among them could be cited the use of Shellac (gum-lac) and coatings based on cellulose polymers, such as hydroxypropylmethylcellulose, with stearic acid.
Therefore, there remains to be found a solid formulation for the oral administration of olanzapine that is suitable for commercial utilisation and that permits stabilisation of olanzapine Form I without affecting the bioavailability of the active substance at physiological pH.